Hepatitis C (HCV) belongs to the Flaviviridae family of positive-sense, single-stranded RNA viruses. The HCV genome encodes a polyprotein, that includes 3000 amino acid residues, which is processed into both structural and nonstructural proteins. HCV infection is a significant global health issue; the World Health Organization estimates that over 170 million people carry the HCV infection, which can ultimately result in chronic hepatitis, cirrhosis, and hepatocellular carcinoma. It has been reported that those complications are responsible for about 10,000-20,000 deaths annually in the U.S. alone, and that HCV is the leading cause of advanced liver disease and the leading underlying cause for liver transplantation. Current therapies for HCV infection rely on the combination of interferon-α (IFN) and the nonspecific antiviral medication, ribavirin. This treatment regimen reportedly causes undesirable side effects such as leucopenia, thrombocytopenia, and hemolytic anemia, with the added disadvantage that only about 40% of patients achieve a sustained viral response (see, for example, G. M. Lauer, B. D. Walker, N. Engl. J. Med. 2001, 345, 41; C. P. Gordon, P. A. Keller, J. Med. Chem. 2005, 48, 1; S.-L. Tan, A. Pause, Y. Shi, N. Sonenberg, Nat. Rev. Drug Discovery 2002, 1, 867; the foregoing publications, and each additional publication cited herein, are incorporated herein by reference). Thus, more effective and less toxic anti-HCV therapeutics are greatly needed.
It has been discovered that spiro hemiaminals are useful for treating HCV.
In one illustrative embodiment, described herein are substituted Spiro hemiaminals that are effective in the treatment of viral diseases including HCV. In another embodiment, described herein are pharmaceutical compositions comprising the substituted Spiro hemiaminals, and methods for the use of the substituted spiro hemiaminals, including pharmaceutical compositions containing them, in the treatment of viral diseases including HCV.
In another embodiment, described herein is a pharmaceutical composition for treating a viral infection, a composition that includes (a) a therapeutically effective amount of one or more compounds of the formula

or a pharmaceutically acceptable salt thereof, wherein
X is carbonyl or a derivative thereof, or alkylene, heteroalkylene, alkylenecarbonyl, or heteroalkylenecarbonyl, each of which is optionally substituted;
Z is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted;
W is O or S;
RA is independently selected in each instance from the group consisting of H, and alkyl and heteroalkyl, each of which is optionally substituted; where m is independently selected in each instance from the group consisting of 1, 2, and 3;
RB is independently selected in each instance from the group consisting of H, alkyl, heteroalkyl, and a prodrug group;
RC is H; or RC is 1 or 2 substituents independently selected from the group consisting of alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylheteroalkyl, or heteroarylheteroalkyl, each of which is optionally substituted; or RC represents a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted; and
n is independently selected in each instance from the group consisting of 1, 2, and 3; and
(b) one or more pharmaceutically acceptable carriers, diluents, or excipients, or a combination thereof.
In another embodiment, described herein is a composition as described above wherein X is carbonyl or a derivative thereof.
In another embodiment, described herein is a composition as described above wherein X is alkylene or heteroalkylene, each of which is optionally substituted.
In another embodiment, described herein is a composition as described above wherein X is alkylenecarbonyl or heteroalkylenecarbonyl, each of which is optionally substituted.
In another embodiment, described herein is a composition as described above wherein X is alkylene, each of which is optionally substituted.
In another embodiment, described herein is a composition as described above wherein X is methylene.
In another embodiment, described herein is a composition as described above wherein Z is aryl or heteroaryl, each of which is optionally substituted.
In another embodiment, described herein is a composition as described above wherein Z is monocyclic aryl or heteroaryl, each of which is optionally substituted.
In another embodiment, described herein is a composition as described above wherein Z is bicyclic aryl or heteroaryl, each of which is optionally substituted.
In another embodiment, described herein is a composition as described above wherein W is O.
In another embodiment, described herein is a composition as described above wherein m is independently selected in each instance from the group consisting of 1 and 2.
In another embodiment, described herein is a composition as described above wherein m is 1 in each instance.
In another embodiment, described herein is a composition as described above wherein each RA is H.
In another embodiment, described herein is a composition as described above wherein each RB is independently H or a prodrug group.
In another embodiment, described herein is a composition as described above wherein each RB is H.
In another embodiment, described herein is a composition as described above wherein RC represents a fused cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted.
In another embodiment, described herein is a composition as described above wherein RC represents a fused optionally substituted aryl or optionally substituted aryl heteroaryl.
In another embodiment, described herein is a composition as described above wherein RC represents a fused optionally substituted aryl.
In another embodiment, described herein is a composition as described above wherein n is independently selected in each instance from the group consisting of 1 and 2.
In another embodiment, described herein is a composition as described above wherein n is 1 in each instance.
In another embodiment, described herein is a composition as described above wherein the compound has the following relative stereochemistry

In another embodiment, described herein is a composition as described above wherein the compound has the following absolute stereochemistry

In another embodiment, described herein is a method for treating a viral infection in a patient, the method comprising the step of administering to the patient a therapeutically effective amount of one or more of the compounds described above, or a therapeutically effective amount of one or more of the compositions described above.
In another embodiment, described herein is the use in the manufacture of a medicament for treating a viral infection (a) a therapeutically effective amount of one or more of the compounds described above; or (b) a therapeutically effective amount of one or more of the compositions described above.
In another embodiment, described herein is the composition, method, or use as described above wherein the viral infection is a hepatitis C viral infection.
In addition, various genera and subgenera of each of X, Z, W, RA, RB, RC, and n are described herein. It is to be understood that all possible combinations of the various genera and subgenera of each of X, Z, W, RA, RB, RC, and n described herein represent additional illustrative embodiments of compounds of the invention described herein. It is to be further understood that each of those additional illustrative embodiments of compounds may be used in any of the compositions, methods, and/or uses described herein.
In another embodiment, pharmaceutical compositions containing one or more of the compounds are also described herein. In another embodiment, pharmaceutical compositions are in the form of a unitary dose, unit dose, or unit dosage form. the In one aspect, the compositions, such as unit doses or unit dosage forms, include a therapeutically effective amount of the one or more compounds for treating a patient with HCV. It is to be understood that the compositions may include other components and/or ingredients, including, but not limited to, other therapeutically active compounds, and/or one or more carriers, diluents, excipients, and the like. In another embodiment, methods for using the compounds and pharmaceutical compositions for treating patients with HCV are also described herein. In one aspect, the methods include the step of administering one or more of the compounds and/or compositions described herein to a patient with HCV. In another aspect, the methods include administering a therapeutically effective amount of the one or more compounds and/or compositions described herein for treating patients with HCV. In another embodiment, uses of the compounds and compositions in the manufacture of a medicament for treating patients with HCV are also described herein. In one aspect, the medicaments include a therapeutically effective amount of the one or more compounds and/or compositions for treating a patient with HCV.
It is to be understood that the compounds described herein may be used alone or in combination with other compounds useful for treating HCV, including those compounds that may be therapeutically effective by the same or different modes of action. In addition, it is to be understood that the compounds described herein may be used in combination with other compounds that are administered to treat other symptoms of HCV.